Bupropion dosage forms with reduced food and alcohol dosing effects

ABSTRACT

This disclosure relates to dosage forms comprising bupropion hydrochloride, another salt form of bupropion, or the free base form of bupropion; dextromethorphan hydrobromide, another salt form of dextromethorphan, or the free base form of dextromethorphan, and a polymer. In some embodiments, the dosage form has no significant dose dumping of bupropion in the presence of ethanol in vitro. In some embodiments, the dosage form does not have a food effect for bupropion or dextromethorphan when taken with a high-fat meal in human subjects. Some embodiments include a method of treating a nervous system condition (such as depression, e.g., major depressive disorder, including treatment-resistant depression, agitation associated with Alzheimer&#39;s disease (or agitation associated with dementia of the Alzheimer&#39;s type), agitation associated with dementia, anxiety (or generalized anxiety disorder), neuropathic pain, or peripheral diabetic neuropathic pain) comprising, administering a dosage form described herein to a human being in need thereof.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.18/157,393, filed Jan. 20, 2023; which claims priority to U.S.Provisional Patent Application No. 63/357,521, filed Jun. 30, 2022, U.S.Provisional Patent Application No. 63/370,590, filed Aug. 5, 2022, andU.S. Provisional Patent Application No. 63/370,771, filed Aug. 8, 2022,all of which are incorporated by reference herein in their entireties.

FIELD

This disclosure relates to dosage forms containing bupropion, optionallyin the presence of dextromethorphan, and use of these dosage forms forvarious therapeutic purposes.

SUMMARY

This disclosure relates to dosage forms comprising bupropionhydrochloride, another salt form of bupropion, or the free base form ofbupropion; dextromethorphan hydrobromide, another salt form ofdextromethorphan, or the free base form of bupropion, and a polymer. Insome embodiments, the dosage form has no significant dose dumping ofbupropion in the presence of ethanol in vitro. In some embodiments, thedosage form does not have a food effect for bupropion when taken with ahigh-fat meal in human subjects. In some embodiments, the dosage formdoes not have a food effect for dextromethorphan when taken with ahigh-fat meal in human subjects.

Some embodiments include a dosage form comprising: 105 mg of bupropionhydrochloride, or a molar equivalent amount of another salt form ofbupropion or the free base form of bupropion, 45 mg of dextromethorphanhydrobromide, or a molar equivalent amount of another salt form ofdextromethorphan or the free base form of dextromethorphan, and apolymer, wherein the dosage form, in the presence of ethanol in vitro,shows no significant dose dumping of bupropion.

Some embodiments include a method of treating a nervous system condition(such as depression, e.g., major depressive disorder, includingtreatment-resistant depression, agitation associated with Alzheimer'sdisease (or agitation associated with dementia of the Alzheimer's type),agitation associated with dementia, anxiety (or generalized anxietydisorder), neuropathic pain, or peripheral diabetic neuropathic pain)comprising administering, once a day or twice a day, a dosage form to ahuman patient in need thereof, wherein the dosage form comprises 105 mgof bupropion hydrochloride, or a molar equivalent amount of another saltform of bupropion or the free base form of bupropion, 45 mg ofdextromethorphan hydrobromide, or a molar equivalent amount of anothersalt form of dextromethorphan or the free base form of dextromethorphan,and a polymer, and wherein the dosage form, in the presence ethanol invitro, shows no significant dose dumping of bupropion.

Some embodiments include a method of treating a nervous system condition(such as depression, e.g., major depressive disorder, agitationassociated with Alzheimer's disease (or agitation associated withdementia of the Alzheimer's type), agitation associated with dementia,anxiety (or generalized anxiety disorder), neuropathic pain, orperipheral diabetic neuropathic pain) comprising administering, once aday or twice a day, a dosage form to a human patient in need thereof,wherein the dosage form comprises 105 mg of bupropion hydrochloride, ora molar equivalent amount of another salt form of bupropion or the freebase form of bupropion, 45 mg of dextromethorphan hydrobromide, or amolar equivalent amount of another salt form of dextromethorphan or thefree base form of dextromethorphan, and a polymer, and wherein thepatient consumes alcohol on a day that the dosage form is administered.

Some embodiments include a method of treating a nervous system condition(such as depression, e.g., major depressive disorder, agitationassociated with Alzheimer's disease (or agitation associated withdementia of the Alzheimer's type), agitation associated with dementia,anxiety (or generalized anxiety disorder), neuropathic pain, orperipheral diabetic neuropathic pain) in a human patient who isconsuming alcohol, comprising administering, once a day or twice a day,a dosage form to a human patient in need thereof, and limiting but notdiscontinuing consumption of alcohol by the human patient, wherein thedosage form comprises 105 mg of bupropion hydrochloride, or a molarequivalent amount of another salt form of bupropion or the free baseform of bupropion, 45 mg of dextromethorphan hydrobromide, or a molarequivalent amount of another salt form of dextromethorphan or the freebase form of dextromethorphan, and a polymer.

Some embodiments include a method of treating a nervous system condition(such as depression, e.g., major depressive disorder, agitationassociated with Alzheimer's disease (or agitation associated withdementia of the Alzheimer's type), agitation associated with dementia,anxiety (or generalized anxiety disorder), neuropathic pain, orperipheral diabetic neuropathic pain) in a human patient who isconsuming alcohol, comprising administering, once a day or twice a day,a dosage form to a human patient in need thereof, and reducing but notdiscontinuing consumption of alcohol by the human patient, wherein thedosage form comprises 105 mg of bupropion hydrochloride, or a molarequivalent amount of another salt form of bupropion or the free baseform of bupropion, 45 mg of dextromethorphan hydrobromide, or a molarequivalent amount of another salt form of dextromethorphan or the freebase form of dextromethorphan, and a polymer.

Some embodiments include a method of treating a nervous system condition(such as depression, e.g., major depressive disorder, agitationassociated with Alzheimer's disease (or agitation associated withdementia of the Alzheimer's type), agitation associated with dementia,anxiety (or generalized anxiety disorder), neuropathic pain, orperipheral diabetic neuropathic pain) in a human patient who isconsuming alcohol, comprising administering, once a day or twice a day,a dosage form to a human patient in need thereof, and minimizing but notdiscontinuing consumption of alcohol by the human patient, wherein thedosage form comprises 105 mg of bupropion hydrochloride, or a molarequivalent amount of another salt form of bupropion or the free baseform of bupropion, 45 mg of dextromethorphan hydrobromide, or a molarequivalent amount of another salt form of dextromethorphan or the freebase form of dextromethorphan, and a polymer.

Some embodiments include a method of treating major depressive disorderin an adult human patient who is consuming alcohol, comprisingadministering, once a day or twice a day, a dosage form to a humanpatient in need thereof, wherein the dosage form comprises 105 mg ofbupropion hydrochloride, or a molar equivalent amount of another saltform of bupropion or the free base form of bupropion, 45 mg ofdextromethorphan hydrobromide, or a molar equivalent amount of anothersalt form of dextromethorphan or the free base form of dextromethorphan,and a polymer; wherein if the human patient is a male, the human patientis consuming two servings or less of alcohol per day; and if the humanpatient is a female, the human patient is consuming one serving or lessof alcohol per day.

Some embodiments include a method of treating major depressive disordercomprising, administering a dosage form described herein to a humanbeing in need thereof. In some embodiments, the dosage form is takenwith an alcoholic beverage. In some embodiments, the dosage form istaken with a high-fat meal.

DETAILED DESCRIPTION

Dose dumping is a phenomenon in which relatively a large amount of drugin a controlled release formulation is quickly released and apotentially toxic quantity of the drug is introduced into systemiccirculation.

A pharmaceutical composition or dosage form described herein mayinclude, or be prepared from, any suitable form of bupropion, such as asalt form, e.g., bupropion hydrochloride, the free base form, hydrates,solvates, polymorphs, other solid forms, etc. In some embodiments, thepharmaceutical composition is free of any other active pharmaceuticalagents.

The pharmaceutical dosage form may include any suitable amount ofbupropion, such as about 90-100 mg, about 100-110 mg, about 110-120 mg,about 103-107 mg, or about 105 mg of the bupropion, such as bupropionhydrochloride, a molar equivalent amount of another salt form ofbupropion, or the free base form of bupropion.

The chemical name of bupropion hydrochloride is:(±)-1-(3-chlorophenyl)-2-[(1,1-dimethylethyl)amino]-1-propanonehydrochloride. Bupropion hydrochloride has the empirical formulaC₁₃H¹⁸ClNO·HCl and a molecular weight of 276.2 (239.74 bupropion base).The structural formula is:

Bupropion hydrochloride powder is white and highly soluble in water.

A pharmaceutical composition or dosage form described herein mayinclude, or be prepared from, any suitable form of dextromethorphan,such as a salt form, e.g., dextromethorphan hydrobromide, the free baseform, hydrates, solvates, polymorphs, other solid forms, etc. In someembodiments, the pharmaceutical composition is free of any other activepharmaceutical agents.

The pharmaceutical dosage form may include any suitable amount ofdextromethorphan, such as about 30-60 mg, about 30-50 mg, about 30-34mg, about 34-38 mg, about 38-42 mg, about 42-46 mg, about 46-50 mg,about 40-45 mg, about 45-50 mg, about 44-46 mg, or about 45 mg of thedextromethorphan, such as bupropion hydrochloride, a molar equivalentamount of another salt form of dextromethorphan, or the free base formof dextromethorphan.

The chemical name of dextromethorphan hydrobromide is morphinan,3-methoxy-17-methyl-, (9a, 13a, 14a), hydrobromide monohydrate.Dextromethorphan hydrobromide has the empirical formula C₁₈H₂₅NO·HBr·H₂Oand a molecular weight of 370.33 (271.4 dextromethorphan base). Thestructural formula is:

Dextromethorphan hydrobromide powder is white or almost white,crystalline, and sparingly soluble in water.

In some embodiments, the dosage form may contain bupropion anddextromethorphan, and no other active pharmaceutical ingredients. Insome embodiments, the bupropion and the dextromethorphan are in twodifferent layers or phases of the dosage form, e.g., each layer containsonly bupropion or dextromethorphan and none of the other.

The pharmaceutical composition or dosage form may include cysteine(e.g., L-cysteine), such as about 30-100 mg, or about 50-100 mg of thecysteine, such as L-cysteine hydrochloride, another salt form ofL-cysteine, or the neutral or zwitterionic form of L-cysteine. Cysteinein these amounts may be helpful in stabilizing bupropion in the presenceof other excipients.

The pharmaceutical composition or dosage form may further comprise asustained release or controlled release polymer, such as a crosslinkedor uncrosslinked acrylate polymer or copolymer (including a poly(acrylicacid) or a poly(alkacrylic acid), such as poly(methacrylic acid), e.g.,a carbomer homopolymer Type A such as Carbopol 971P), a cellulosederivative, such as methylcellulose, etc. In some embodiments, thecontrolled release polymer (e.g., a carbomer copolymerType A) is about1-40%, about 1-5%, about 5-10%, about 10-15%, about 15-20%, about20-30%, about 30-40%, about 11-13%, or about 12% of the weight of thepharmaceutical composition. In some embodiments, the controlled releasepolymer is about 0.1-20%, about 0.1-2%, about 2-4%, about 4-6%, about6-8%, about 8-10%, about 10-15%, about 15-20%, or about 7% of the weightof the dosage form.

The pharmaceutical composition or dosage form may further comprise afiller such as microcrystalline cellulose. In some embodiments, thefiller may be about 20-60%, about 20-30%, about 30-40%, about 40-50%, orabout 50-60% of the weight of the pharmaceutical composition or thedosage form.

The pharmaceutical composition or dosage form may further comprise alubricant such as magnesium stearate. In some embodiments, the lubricantis about 0.1-10%, about 0.1-2%, about 2-4%, about 4-6%, about 6-8%, orabout 8-10% of the weight of the pharmaceutical composition or thedosage form.

The dosage form may be formulated for any suitable route ofadministration, such as oral administration.

Dosage forms, such as solid dosage forms, e.g. capsules, tablets, orpills, for oral administration may also contain one or more of thefollowing: a binder such as gum tragacanth, acacia, corn starch, orgelatin; an excipient, such as dicalcium phosphate; a disintegratingagent such as corn starch, potato starch, alginic acid, and the like; asweetening agent such as sucrose, lactose, or saccharin; or a flavoringagent such as peppermint, oil of wintergreen, or cherry flavoring. Whenthe dosage form is a capsule, it may contain, in addition to materialsof the above type, a liquid carrier. Various other materials may bepresent as a coating, for example, tablets, pills, or capsules may becoated with shellac, sugar, or both. It may be desirable for material ina dosage form or pharmaceutical composition to be pharmaceutically pureand nontoxic in the amounts employed.

In some embodiments, the dosage form contains cysteine, Carbopol 971P,microcrystalline cellulose, silicon dioxide, and magnesium. In someembodiments, the dosage form contains a first layer comprising bupropionand cysteine, and a second layer comprising dextromethorphan,microcrystalline cellulose, croscarmellose sodium, and magnesiumstearate.

An example of a single layer dosage form is show below:

Layer 1

Layer 1 Amount Ingredient (mg) Bupropion  90-120 Cysteine  30-100Carbopol 971P 20-60 Microcrystalline Cellulose 200-300 Colloidal SiliconDioxide  1-10 Magnesium Stearate  1-10

A two layer dosage form may contain a first layer with the compositionshown above (Layer 1), and a second layer detailed below (Layer 2).

Layer 2

Layer 2 Amount Ingredient (mg) Dextromethorphan 30-60 MicrocrystallineCellulose 100-150 Croscarmellose sodium  1-20 Magnesium Stearate  1-10

In some embodiments, the dosage form may be for oral administration andmay be a round bilayer tablet. Each tablet may contain 45 mgdextromethorphan hydrobromide (equivalent to 32.98 mg dextromethorphanbase) in an immediate-release formulation and 105 mg bupropionhydrochloride (equivalent to 91.14 mg bupropion base) in anextended-release formulation. Each tablet may further contain any, orall, of the following inactive ingredients: carbomer homopolymer,colloidal silicon dioxide, crospovidone, glyceryl monocaprylocaprate,I-cysteine hydrochloride monohydrate, magnesium stearate,microcrystalline cellulose, polyvinyl alcohol, red iron oxide, sodiumlauryl sulfate, stearic acid, talc, titanium dioxide, and/or yellow ironoxide. The pharmaceutical compositions or dosage forms described hereinmay be useful in treating neurological disorders or psychiatricconditions, such as depression, including major depressive disorder ortreatment-resistant major depressive disorder, agitation, such asagitation associated with Alzheimer's disease, addiction, such asnicotine addiction, etc. For example, the pharmaceutical composition ofdosage form may be administered once or twice a day to a human beingsuffering from a neurological disorder or psychiatric condition.Treatment may be continued as needed while the treatment is effectiveand safe, e.g., for at least 1 week, at least 4 weeks, at least onemonth, at least 2 months, at least 3 months, at least 6 months, at least1 year, 1 week to 2 months, 1-3 months, 3-6 months, 6-12 months, 1-2years, or possibly longer.

Due to US Food and Drug Administration (FDA) concern of dose dumping ofbupropion hydrochloride when taken with ethanol, the FDA currentlyrequests that dissolution testing on dosage forms containing bupropionbe conducted using various concentrations of ethanol in the dissolutionmedium, as follows:

-   -   Testing Conditions: 900 mL, 0.1 N HCl, USP apparatus 2 (paddle)        at 50 rpm, with or without ethanol;    -   Test 1: 12 units tested according to the proposed method (with        0.1N HCl), with data collected every 15 minutes for a total of 2        hours;    -   Test 2: 12 units analyzed by substituting 5% (v/v) of test        medium with Alcohol USP (ethanol) and data collection every 15        minutes for a total of 2 hours;    -   Test 3: 12 units analyzed by substituting 20% (v/v) of test        medium with Alcohol USP (ethanol) and data collection every 15        minutes for a total of 2 hours; and    -   Test 4: 12 units analyzed by substituting 40% (v/v) of test        medium with Alcohol USP (ethanol) and data collection every 15        minutes for a total of 2 hours.

According to the FDA, both test and reference products must be testedaccordingly, and data must be provided on individual unit, means, rangeand % CV on both strengths. (FDA Draft Guidance on BupropionHydrochloride, p. 2.)

LITERATURE EXAMPLES

According to FDA documents the bupropion product Forfivo XL was testedfor ethanol dose dumping. (Center for Drug Evaluation and Research,Application No. 022497Orig1s000), CLINICAL PHARMACOLOGY ANDBIOPHARMACEUTICS REVIEW(S) (“Forfivo Resubmission”), p. 17.) The ForfivoResubmission discloses that Forfivo contains bupropion hydrochloride,hydroxypropyl cellulose, hydrochloric acid, polyethylene oxide, stearicacid, colloidal silicon dioxide, magnesium stearate, methacrylic acidcopolymer, talc, polyethylene glycol (PEG) 8000, titanium oxide (TiO₂),and carboxymethylcellulose sodium (NaCMC). (Forfivo Resubmission, p.10). The Forfivo Resubmission further reports that experiment describedabove was conducted for BUP 450 XL tablets. According to the ForfivoResubmission, “[f] or 2 hours, no dissolved bupropion HCl from BUP 450XL tablets was seen at 0% of alcohol. In the presence of 20% of alcohol,7% of dissolved bupropion HCl from BUP 450 XL tablets was observed intwo hours. In the presence of 40% of alcohol, 22% (range of 16-25%) ofdissolved bupropion HCl from BUP 450 XL tablets was seen in two hours.The drug product is showing dose dumping with alcohol in vitro.” (p. 17)

According to the CONTRAVE label, when a dosage form containing 8 mg ofnaltrexone HCl, 90 mg of bupropion HCl, microcrystalline cellulose,hydroxypropyl cellulose, lactose anhydrous, L-cysteine hydrochloride,crospovidone, magnesium stearate, hypromellose, edetate disodium,lactose monohydrate, colloidal silicon dioxide, Opadry II Blue, and FD&CBlue #2 aluminum lake was administered with a high-fat meal, the AUC andC_(max) for naltrexone increased 2.1-fold and 3.7-fold, respectively,and the AUC and C_(max) for bupropion increased 1.4-fold and 1.8-fold,respectively. At steady state, the food effect increased AUC and C_(max)for naltrexone by 1.7-fold and 1.9-fold, respectively, and increased AUCand C_(max) for bupropion by 1.1-fold and 1.3-fold, respectively. Thus,the label indicates that CONTRAVE should not be taken with high-fatmeals because of the resulting significant increases in bupropion andnaltrexone systemic exposure.

The subject combination may be used for adjunctive treatment of majordepressive disorder or depression.

In addition to major depressive disorder, the subject combination may beused to treat other diseases in conditions in the patient populations orcircumstances described herein. For example, the subject combination maybe used to treat pain or a neurological disorder. Examples ofneurological disorders that may be treated with the subject combinationinclude, but are not limited to: affective disorders, psychiatricdisorders, cerebral function disorders, movement disorders, dementias,motor neuron diseases, neurodegenerative diseases, seizure disorders,and headaches.

Affective disorders that may be treated by the subject combinationinclude, but are not limited to, depression, major depression, treatmentresistant depression, treatment resistant bipolar depression, bipolardisorders including cyclothymia, seasonal affective disorder, mooddisorders, chronic depression (dysthymia), psychotic depression,postpartum depression, premenstrual dysphoric disorder (PMDD),situational depression, atypical depression, mania, anxiety disorders,attention deficit disorder (ADD), attention deficit disorder withhyperactivity (ADDH), and attention deficit/hyperactivity disorder(AD/HD), bipolar and manic conditions, obsessive-compulsive disorder,bulimia, obesity or weight-gain, narcolepsy, chronic fatigue syndrome,premenstrual syndrome, substance addiction or abuse, nicotine addiction,psycho-sexual dysfunction, pseudobulbar affect, and emotional lability.

Depression may be manifested by depressive symptoms. These symptoms mayinclude psychological changes such as changes in mood, feelings ofintense sadness, despair, mental slowing, loss of concentration,pessimistic worry, agitation, anxiety, irritability, guilt, anger,feelings of worthlessness, reckless behavior, suicidal thoughts, orattempts, and/or self-deprecation. Physical symptoms of depression mayinclude insomnia, anorexia, appetite loss, weight loss, weight gain,decreased energy and libido, fatigue, restlessness, aches, pains,headaches, cramps, digestive issues, and/or abnormal hormonal circadianrhythms.

Psychiatric disorders that may be treated by the subject combination,include, but are not limited to, anxiety disorders, including but notlimited to, phobias, generalized anxiety disorder, social anxietydisorder, panic disorder, agoraphobia, obsessive-compulsive disorder,and post-traumatic stress disorder (PTSD); mania, manic depressiveillness, hypomania, unipolar depression, depression, stress disorders,somatoform disorders, personality disorders, psychosis, schizophrenia,delusional disorder, schizoaffective disorder, schizotypy, aggression,aggression in Alzheimer's disease, agitation, and agitation inAlzheimer's disease. Alzheimer's disease may also be referred to asdementia of the Alzheimer's type. Other neurobehavioral symptoms ofAlzheimer's disease that may be treated include disinhibition andapathy.

Agitation in Alzheimer's disease occurs as the disease progresses.Agitation may present itself as inappropriate verbal, emotional, and/orphysical behaviors. Inappropriate behaviors may include, but are notlimited to, incoherent babbling, inappropriate emotional response,demands for attention, threats, irritability, frustration, screaming,repetitive questions, mood swings, cursing, abusive language, physicaloutbursts, emotional distress, restlessness, shredding, sleepingdisturbances, delusions, hallucinations, pacing, wandering, searching,rummaging, repetitive body motions, hoarding, shadowing, hitting,scratching, biting, combativeness, hyperactivity, and/or kicking.

Alzheimer's disease (AD) is a progressive neurodegenerative disordercharacterized by cognitive decline, and behavioral and psychologicalsymptoms including agitation. AD is the most common form of dementia andafflicts an estimated 6 million individuals in the United States, anumber that is anticipated to increase to approximately 14 million by2050. Agitation is reported in up to 70% of patients with AD and ischaracterized by emotional distress, aggressive behaviors, disruptiveirritability, and disinhibition. Managing agitation is a priority in AD.Agitation in patients with AD has been associated with increasedcaregiver burden, decreased functioning, accelerated cognitive decline,earlier nursing home placement, and increased mortality. There arecurrently no therapies approved by the FDA for the treatment ofagitation in patients with AD.

Neurobehavioral symptoms have been known to appear during dementia andmay be treated by the combination. Caregivers or families may feel moreoverwhelmed by patients' behavioral/psychological symptoms than by theircognitive impairment. Common forms of the syndrome are Alzheimer'sdisease, vascular dementia, dementia with Lewy bodies (abnormalaggregates of protein that develop inside nerve cells), and a group ofdiseases that contribute to frontotemporal dementia (degeneration of thefrontal lobe of the brain). The symptoms that dementia patients have aresimilar to those of psychiatric disorders, but some are slightlydifferent from each other. Neurobehavioral symptoms associated withdementia include depression, apathy, agitation, disinhibition,hallucinations, delusions, psychosis, impulsiveness, aggressiveness,compulsion, excessive sex drive, and personality disorders.Neurobehavioral symptoms such as disinhibition may also be found inother conditions such as traumatic brain injury.

Agitation in patients with Alzheimer's disease may be assessed using theCohen Mansfield Agitation Inventory or CMAI. The CMAI assesses variousbehaviors including, Hitting (including self), Kicking, Grabbing ontopeople, Pushing, Throwing things, Biting, Scratching, Spitting, Hurtingself or others, Tearing things or destroying property, Making physicalsexual advances, Pacing, aimless wandering, Inappropriate dress ordisrobing, Trying to get to a different place, Intentional falling,Eating/drinking inappropriate substances, Handling thingsinappropriately, Hiding things, Hoarding things, Performing repetitivemannerisms, General restlessness, Screaming, Making verbal sexualadvances, Cursing or verbal aggression, Repetitive sentences orquestions, Strange noises (weird laughter or crying), Complaining,Negativism, Constant unwarranted request for attention or help.

Schizophrenia may be treated by the combination including positivesymptoms and/or negative symptoms of schizophrenia, or residual symptomsof schizophrenia. Other conditions that may treated include intermittentexplosive disorder.

Cerebral function disorders that may be treated by the subjectcombination include, but are not limited to, disorders involvingintellectual deficits such as senile dementia, Alzheimer's typedementia, memory loss, amnesia/amnestic syndrome, epilepsy, disturbancesof consciousness, coma, lowering of attention, speech disorders, voicespasms, Parkinson's disease, Lennox-Gastaut syndrome, autism,hyperkinetic syndrome, and schizophrenia. Cerebral function disordersalso include disorders caused by cerebrovascular diseases including, butnot limited to, stroke, cerebral infarction, cerebral bleeding, cerebralarteriosclerosis, cerebral venous thrombosis, head injuries, and thelike where symptoms include disturbance of consciousness, seniledementia, coma, lowering of attention, and speech disorders.

Substance addiction abuse that may be treated by the subject combinationincludes, but is not limited to, drug dependence, addiction to cocaine,psychostimulants (e.g., crack, cocaine, speed, meth), nicotine, alcohol,opioids, anxiolytic and hypnotic drugs, Cannabis (marijuana),amphetamines, hallucinogens, phencyclidine, volatile solvents, andvolatile nitrites. Nicotine addiction includes nicotine addiction of allknown forms, such as smoking cigarettes, cigars and/or pipes,e-cigarettes or vaping, and addiction to chewing tobacco.

Movement disorders that may be treated by the subject combinationinclude, but are not limited to, akathisia, akinesia, associatedmovements, athetosis, ataxia, ballismus, hemiballismus, bradykinesia,cerebral palsy, chorea, Huntington's disease, Huntington's diseasechorea, rheumatic chorea, Sydenham's chorea, dyskinesia, tardivedyskinesia, dystonia, blepharospasm, spasmodic torticollis,dopamine-responsive dystonia, Parkinson's disease, restless legssyndrome (RLS), tremor, essential tremor, and Tourette's syndrome, andWilson's disease.

Dementias that may be treated by the subject combination include, butare not limited to, Alzheimer's disease, Parkinson's disease, vasculardementia, dementia with Lewy bodies, mixed dementia, fronto-temporaldementia, Creutzfeldt-Jakob disease, normal pressure hydrocephalus,Huntington's disease, Wernicke-Korsakoff Syndrome, and Pick's disease.

Motor neuron diseases that may be treated by the subject combinationinclude, but are not limited to, amyotrophic lateral sclerosis (ALS),progressive bulbar palsy, primary lateral sclerosis (PLS), progressivemuscular atrophy, post-polio syndrome (PPS), spinal muscular atrophy(SMA), spinal motor atrophies, Tay-Sach's disease, Sandoff disease, andhereditary spastic paraplegia.

Neurodegenerative diseases that may be treated the subject combinationinclude, but are not limited to, Alzheimer's disease, prion-relateddiseases, cerebellar ataxia, spinocerebellar ataxia (SCA), spinalmuscular atrophy (SMA), bulbar muscular atrophy, Friedrich's ataxia,Huntington's disease, Lewy body disease, Parkinson's disease,amyotrophic lateral sclerosis (ALS or Lou Gehrig's disease), multiplesclerosis (MS), multiple system atrophy, Shy-Drager syndrome,corticobasal degeneration, progressive supranuclear palsy, Wilson'sdisease, Menkes disease, adrenoleukodystrophy, cerebral autosomaldominant arteriopathy with subcortical infarcts and leukoencephalopathy(CADASIL), muscular dystrophies, Charcot-Marie-Tooth disease (CMT),familial spastic paraparesis, neurofibromatosis, olivopontine cerebellaratrophy or degeneration, striatonigral degeneration, Guillain-Barrésyndrome, and spastic paraplesia.

Seizure disorders that may be treated by the subject combinationinclude, but are not limited to, epileptic seizures, nonepilepticseizures, epilepsy, febrile seizures; partial seizures including, butnot limited to, simple partial seizures, Jacksonian seizures, complexpartial seizures, and epilepsia partialis continua; generalized seizuresincluding, but not limited to, generalized tonic-clonic seizures,absence seizures, atonic seizures, myoclonic seizures, juvenilemyoclonic seizures, and infantile spasms; and status epilepticus.

Types of headaches that may be treated by the subject combinationinclude, but are not limited to, migraine, tension, and clusterheadaches.

Other neurological disorders that may be treated by the subjectcombination include, Rett Syndrome, autism, tinnitus, disturbances ofconsciousness disorders, sexual dysfunction, intractable coughing,narcolepsy, cataplexy; voice disorders due to uncontrolled laryngealmuscle spasms, including, but not limited to, abductor spasmodicdysphonia, adductor spasmodic dysphonia, muscular tension dysphonia, andvocal tremor; diabetic neuropathy, chemotherapy-induced neurotoxicity,such as methotrexate neurotoxicity; incontinence including, but notlimited, stress urinary incontinence, urge urinary incontinence, andfecal incontinence; and erectile dysfunction.

In some embodiments, the subject combination may be used to treat pain,joint pain, pain associated with sickle cell disease, pseudobulbaraffect, depression (including treatment resistant depression), disordersrelated to memory and cognition, schizophrenia, Parkinson's disease,amyotrophic lateral sclerosis (ALS), Rhett's syndrome, seizures, cough(including chronic cough), etc.

In some embodiments, the subject combination may be administered orallyto relieve musculoskeletal pain including low back pain, and painassociated with rheumatoid arthritis, juvenile rheumatoid arthritis,osteoarthritis, erosive osteoarthritis, sero-negative (non-rheumatoid)arthropathies, non-articular rheumatism, peri-articular disorders, axialspondyloarthritis including ankylosing spondylitis, Paget's disease,fibrous dysplasia, SAPHO syndrome, transient osteoarthritis of the hip,vertebral crush fractures, osteoporosis, etc.

In some embodiments, the subject combination may be administered torelieve inflammatory pain including musculoskeletal pain, arthritispain, and complex regional pain syndrome.

Arthritis refers to inflammatory joint diseases that can be associatedwith pain. Examples of arthritis pain include pain associated withosteoarthritis, erosive osteoarthritis, rheumatoid arthritis, juvenilerheumatoid arthritis, sero-negative (non-rheumatoid) arthropathies,non-articular rheumatism, peri-articular disorders, neuropathicarthropathies including Charcot's foot, axial spondyloarthritisincluding ankylosing spondylitis, and SAPHO syndrome.

In some embodiments, the subject combination is used to treat chronicmusculoskeletal pain.

In some embodiments, the subject composition may be administered torelieve complex regional pain syndrome, such as complex regional painsyndrome type I (CRPS-1), complex regional pain syndrome type II(CRPS-II), CRPS-NOS, or another type of CRPS. CRPS is a type ofinflammatory pain. CRPS can also have a neuropathic component. Complexregional pain syndrome is a debilitating pain syndrome. It ischaracterized by severe pain in a limb that can be accompanied by edema,and autonomic, motor, and sensory changes.

In some embodiments, the subject composition may be administered orallyto relieve neuropathic pain.

Examples of neuropathic pain include pain due to diabetic peripheralneuropathy or diabetic peripheral neuropathic pain, post-herpeticneuralgia, trigeminal neuralgia, monoradiculopathies, phantom limb pain,central pain, pain due to multiple sclerosis, etc. Other causes ofneuropathic pain include cancer-related pain, lumbar nerve rootcompression, spinal cord injury, post-stroke pain, central multiplesclerosis pain, HIV-associated neuropathy, and radio- or chemo-therapyassociated neuropathy, etc.

In some embodiments, the subject composition may be administered torelieve fibromyalgia.

The term “treating”, or “treatment” includes the diagnosis, cure,mitigation, treatment, or prevention of disease in man or other animals,or any activity that otherwise affects the structure or any function ofthe body of man or other animals.

A subject combination may be used to treat any disease or conditionidentified as treatable by the combination of bupropion anddextromethorphan in any of the following U.S. Pat. Nos. 8,569,328,9,168,234, 9,189,905 9,205,083, 9,238,032, 9,278,095, 9,314,462,9,370,513, 9,375,429, 9,408,815, 9,421,176, 9,457,023, 9,457,025,9,474,731, 9,486,450, 9,700,528, 9,700,553, 9,707,191, 9,763,932,9,861,595, 9,867,819, 9,968,568, 10,058,518, 10,064,857, 10,080,727,10,092,560, 10,092,561, 10,105,327, 10,105,361, 10,251,879, 10,463,634,10,512,643, 10,548,857, 10,596,167, 10,772,850, 10,780,064, 10,780,066,10,786,469, 10,786,496, 10,799,497, 10,806,710, 10,864,209, 10,874,663,10,874,664, 10,874,665, 10,881,624, 10,881,657, 10,894,046, 10,894,047,10,898,453, all of which are incorporated by reference herein in theirentireties for their disclosure of diseases that may be treated by acombination of bupropion and dextromethorphan, including specificembodiments and combinations described therein.

As illustrated in the examples below, the subject combination has nodose dumping of bupropion in the presence of ethanol in vitro. As aresult, patients may use alcohol as long as the use is minimized orlimited. For example, an adult female may consume one serving of alcoholor less per day (such as one serving per day, 4 servings per week orless, 3 servings per week or less, 1 serving per week or less, 1 servingper month or less, 1 serving per year or less, etc.) or an adult malemay consume two servings of alcohol or less per day (such as twoservings per day, one serving per day, 4 servings per week or less, 3servings per week or less, 1 serving per week or less, 1 serving permonth or less, 1 serving per year or less, etc.).

Example 1

A two-layer dosage form having Layer 1 and Layer 2 as described above,was tested for ethanol dose dumping as described above. No dose dumpingof bupropion in the presence of ethanol in vitro was observed.

Example 2

A two-layer dosage form having Layer 1 and Layer 2 as described above,was tested for a food effect by administering the dosage form with ahigh-fat meal to human subjects, and comparing the AUC and C_(max) tothat obtained when administered to fasted human subjects. No significantdifference between the two groups was observed in either the AUC or theC_(max) of bupropion or dextromethorphan.

U.S. Provisional Patent Application No. 63/370,771, filed Aug. 8, 2022,is incorporated by reference herein in its entirety.

Unless otherwise indicated, all numbers expressing quantities ofingredients, properties such as amounts, percentage, and so forth usedin the specification and claims are to be understood in all instances asindicating both the exact values as shown and as being modified by theterm “about.” Accordingly, unless indicated to the contrary, thenumerical parameters set forth in the specification and attached claimsare approximations that may vary depending upon the desired propertiessought to be obtained. At the very least, and not as an attempt to limitthe application of the doctrine of equivalents to the scope of theclaims, each numerical parameter should at least be construed in lightof the number of reported significant digits and by applying ordinaryrounding techniques.

Use of the term “comprising” or “comprises” herein also contemplatesthat use of “consisting essentially of,” “consists essentially of,”“consisting of,” or “consists of” in its place.

Affirmative recitation of an element anywhere herein should beunderstood to contemplate both including and excluding that element.

The terms “a,” “an,” “the” and similar referents used in the context ofdescribing the embodiments (especially in the context of the followingclaims) are to be construed to cover both the singular and the plural,unless otherwise indicated herein or clearly contradicted by context.All methods described herein can be performed in any suitable orderunless otherwise indicated herein or otherwise clearly contradicted bycontext. The use of any and all examples, or exemplary language (e.g.,“such as”) provided herein is intended merely to better illuminate theembodiments and does not pose a limitation on the scope of any claim. Nolanguage in the specification should be construed as indicating anynon-claimed element essential to the practice of the claims.

Groupings of alternative elements or embodiments disclosed herein arenot to be construed as limitations. Each group member may be referred toand claimed individually or in any combination with other members of thegroup or other elements found herein. It is anticipated that one or moremembers of a group may be included in, or deleted from a group, forreasons of convenience and/or to expedite prosecution. When any suchinclusion or deletion occurs, the specification is deemed to contain thegroup as modified thus fulfilling the written description of all Markushgroups if used in the appended claims.

Certain embodiments are described herein, including the best mode knownto the inventors for carrying out the claimed embodiments. Of course,variations on these described embodiments will become apparent to thoseof ordinary skill in the art upon reading the foregoing description. Theinventor expects skilled artisans to employ such variations asappropriate, and the inventors intend for the claimed embodiments to bepracticed otherwise than specifically described herein. Accordingly, theclaims include all modifications and equivalents of the subject matterrecited in the claims as permitted by applicable law. Moreover, anycombination of the above-described elements in all possible variationsthereof is contemplated unless otherwise indicated herein or otherwiseclearly contradicted by context.

In closing, it is to be understood that the embodiments disclosed hereinare illustrative of the principles of the claims. Other modificationsthat may be employed are within the scope of the claims. Thus, by way ofexample, but not of limitation, alternative embodiments may be utilizedin accordance with the teachings herein. Accordingly, the claims are notlimited to embodiments precisely as shown and described.

1. A method of avoiding seizures, comprising: 1) selecting a humanpatient with major depressive disorder who is receiving a dosage formtwice a day and is consuming alcohol; and 2) advising the patient tominimize, but not abruptly discontinue, alcohol consumption; wherein thedosage form comprises 105 mg of bupropion hydrochloride, or a molarequivalent amount of another salt form of bupropion or the free baseform of bupropion, 45 mg of dextromethorphan hydrobromide, or a molarequivalent amount of another salt form of dextromethorphan or the freebase form of dextromethorphan, and a polymer.
 2. The method of claim 1,wherein the human patient is an adult male, and the human patientconsumes two servings or less of alcohol per day after alcoholconsumption is advised to minimize.
 3. The method of claim 1, whereinthe human patient is an adult female, and the human patient consumes oneserving or less of alcohol per day after alcohol consumption is advisedto minimize.
 4. The method of claim 1, wherein the dosage form furthercomprises colloidal silicon dioxide.
 5. The method of claim 1, whereinthe dosage form further comprises crospovidone.
 6. The method of claim1, wherein the dosage form further comprises: glycerylmonocaprylocaprate.
 7. The method of claim 1, wherein the dosage formfurther comprises L-cysteine hydrochloride monohydrate.
 8. The method ofclaim 1, wherein the dosage form further comprises magnesium stearate.9. The method of claim 1, wherein the dosage form further comprisesmicrocrystalline cellulose.
 10. The method of claim 1, wherein thedosage form further comprises polyvinyl alcohol.
 11. The method of claim1, wherein the dosage form further comprises sodium lauryl sulfate. 12.The method of claim 1, wherein the dosage form further comprises stearicacid.
 13. The method of claim 1, wherein the dosage form furthercomprises titanium dioxide.
 14. The method of claim 1, wherein thepolymer is a carbomer homopolymer.
 15. The method of claim 1, whereinthe dosage form further comprises: colloidal silicon dioxide,crospovidone, glyceryl monocaprylocaprate, L-cysteine hydrochloridemonohydrate, magnesium stearate, microcrystalline cellulose, polyvinylalcohol, red iron oxide, sodium lauryl sulfate, stearic acid, talc,titanium dioxide, or yellow iron oxide, or a combination thereof.